DK142751B - Analogous Process for Preparation of 4 - ((2-Methyl-3-hydroxy-4-hydroxymethyl) -5-pyridyl-N-methyl-N'-piperazinyl) -p-fluoro-butyrophenone or its acid addition salts. - Google Patents

Description

(IT) PUBLICATION MANUAL 142751 DENMARK <51) lnt · Cl · 3 c 07 ° 213/66 «(21) Application No. 1 680/74 (22) Filed on 27 · HIST · 1 974 (24) Running day $ 7 · mar. 197 ^ (44) The application presented and the petition published on 12th JOH. 1 981

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority granted from it

Mar 28 1975, 14815/75, GB

(71) SOCIETE DE ETUDES DE PRODUCTS CHIMIQUES, 16 rue Kleber, 9215Ο le syles-Moulineauz, FR.

(72) Inventor: Andre Es anu, 119 ru © de la Croix-Nivert, 75015 Paris, FR.

(74) Full consideration of the proceedings:

Hofman-Bang & Boutard Engineering Company.

(54) Analogous process for the preparation of 4- ((2-methyl-5-hydroxy-4-hydroxymethyl) -5-pyridyl-N-methyl-N1-piperazinyl) -p-fluoro-butyropheone or its acid-dithlonal salts.

The present invention relates to an analogous process for the preparation of the novel compound 4 - [(2-methyl-3-hydroxy-4-hydroxymethyl) -5-pyridyl-N-methyl-N '-piperazinyl] -p-fluorobutyrro -phenone of formula CR / M.

0Η _ ^^ \ _ ΟΙ, - i / - (3¾ - (3¾ - (3¾ - C- ^--R

Commonly used acids for preparing the acid addition salts are e.g. hydrochloric, acetic, chloroacetic, benzoic and maleic.

The compounds of the invention exhibit interesting hypotensive and adrenolytic properties, with a pronounced α-blocking effect combined with a hypotensive effect comparable to or often greater than that of reserpine.

To illustrate the process of the invention, the preparation of the maleic acid salt having the empirical formula: C34H4O015N3F ° S molecular weight 749.7 is reviewed. This compound is a beige-yellow powder with m.p. 127-130 ° C, which is water-soluble at room temperature, soluble in hot ethanol and octanol, and insoluble in chloroform.

The process according to the invention, which is characterized by the characterizing part of claim 1, is carried out by reacting 5-piperazinylpyridoxine wherein the hydroxyl groups at the 3 and 4 positions are protected, illustrated by a 3,4-isopropylidenyl group. , with 4-chloro-p-fluoro-butyrophenone in the presence of a suitable solvent, preferably xylene, and optionally in the presence of triethylamine, according to the following reaction scheme:

VFT

VA. / \ / - \ Wj "Y - N Ml + Cl (0¾) 2 - C-f> * F —- ^ - '-' O \ == / xylene

N

CH, O _

VS

æ / \ jS- ^ a- \ y - ^> 3-ξ ^ νΖζν ~ ρ σΐ3 ~ - \ γ ^ ·

The compound thus obtained is reacted to produce the maleic acid salt with maleic acid, which produces an acid addition salt with 3 moles of maleic acid per liter. mole of pyridoxine fluvate and also a breaking of the isopropylidene bridge, which is most easily done by reflux heating.

The process according to the invention is further illustrated by the following detailed example:

EXAMPLE

In a 10 liter reactor equipped with stirring, cooling and heating means was poured 530 g (1.85 mole) of 3,4-isopropylidenyl-5-piperazinylpyridoxine, 480 g (2.4 mole) of 4-chloro p-fluoro-butyrophenone, 240 g (2.4 moles) of triethylamine and 5 liters of anhydrous xylene.

4 142751

After stirring, a complete dissolution of the ingredients in xylene had occurred and the mixture was heated for 15 hours at reflux under which the mixture turned brown and a precipitate formed. The precipitate was separated, filtered, dried, washed and treated with 5 liters of a 90% solution of petroleum ether in diethyl ether to give 550 g of product after drying.

The product was recrystallized from isopropanol to give 460 g of 3,4-isopropylidenyl-pyridoxin-5-yl-4-piperazin-1-yl-p-fluoro-4-butyrophenone, m.p. 114-115 C.

This compound was treated with maleic acid in the same 10 liter reactor as above. Into this reactor was poured 6 liters of distilled water containing 2% ethanol, 400 g (3.4 moles) of maleic acid and 300 g (0.68 moles) of the above-obtained isopropylidene derivative. The mixture was heated under reflux for 30 minutes and then evaporated to dryness under reduced pressure. The residue was treated with ethanol and recrystallized from 3 liters of pure ethanol.

420 g of a beige-yellow product was obtained, m.p. 127-130 ° C and an analysis showed that it corresponded to the formula C ^ H ^ qO-j ^ N ^ F ·

The 3,4-isopropylidenyl-5-piperazinyl-pyridoxine used was prepared by reacting monocarboxyethyl-piperazine with 3,4-isopropylidenyl-5-chloropyridoxine in anhydrous dimethylformamide in the presence of potassium carbonate. The 3,4-isopropylidenyl-5-chloro-pyridoxine used for this purpose was prepared by chlorination of 3,4-isopropylidene-pyridoxine with SO 2 Cl 2, and said pyridoxine can be prepared as described in British Patent No. 1,286,161.

The antihypertensive effect of the compounds of the present invention has been investigated further using the maleic acid addition salt prepared above, hereinafter referred to as Compound A, and rats made renal hypertensive (Goldblatt) and metacorticoid (DOCA) hypertensive respectively. , compared to standard preparations of guanethidine and α-methyldopa. An additional study was conducted on normally hypertensive rats of the Okamoto breed. In the other experiments, male bovine rats (CFY breed) obtained from Carwoth Europe were used. Beads of deoxycprticosterone acetate (DOCA) for implant use were obtained from Organon Laboratories Ltd. Guanethidine sulphate (islet melamine tablets, CXBA), α-methyldopa (Aldomet tablets, MSD) hereinafter referred to as methyldopa were used in the experiments.

APPROACHES

- Preparation of Goldblatt hypertensive rats

This method is analogous to the method described by Goldblatt, H.,

Lynch, J., Hanzal, R.F. & Summerville, W.W. (1934) J.Exp.Med., 59, 347-379 *

Male rats of the Carwoth CFY breed (120-140 g) were used. Under sterile conditions and ether anesthesia, a costolumbar incision was made and the left kidney was pulled down toward the abdomen. The renal stem was exposed and the artery was cut free. A silver clamp was placed around the artery near the abdominal aorta. The right kidney was removed through another incision. The body wall was stitched with catgut and the skin closed with clamps. Each rat was then administered 30,000 IU procaine-penicillin G by intra-muscular route. Hypertension developed slowly over a period of 6-9 weeks.

- Preparation of DOCA hypertensive rats

This approach is analogous to that of Green, D.M., Saunders, F.J., Wahlgren, N. & Craig, R.L. (1952), Am. J. Physiol, 170, 94-106.

Male rats of the Carwoth CFY breed (90-120 g) were used. Under sterile conditions and ether anesthesia, an incision was made in the left side of the abdominal wall of the rat and the left kidney was removed. A 50 mg bullet of DOCA was implanted subcutaneously.

6 142751

The abdominal wall was sewn together with catgut and the skin closed with clamps. Each rat was then administered 30,000 IU procaine-penicillin G by intramuscular route. The drinking water was replaced by 0.8% sodium chloride and 0.1% potassium chloride in tap water.

Hypertension developed slowly over a period of 5-8 weeks.

- Conducting the experiment

The rats were deprived of food but not water for 18 hours before the experiment itself. The blood pressure of each rat was measured before as well as 2, 4, 8 and 24 hours after administration of the compound studied. The compounds were suspended in 1% carboxymethyl cellulose and administered at a dose volume of 10 ml / kg. Groups of 8 animals were used.

Blood pressure was measured indirectly on the tail artery by a modification of the method of Ben-Ziv, G., Weinman J. & Sulman, F.G.

(1964), Arch.int. Eharmacodyn, 149, 527-535 ·

RESULTS

The mean blood pressure of each group before, as well as 2.4.8 and 24 hours after administration of the investigated agents is shown in Table 1 below. The percent change in mean pressure from the value before administration is also shown in Table 1.

The mean systolic and diastolic blood pressure of the groups before and at different times after the administration of the compounds is shown in Table 2 for Goldblatt rats and Table 3 for DOCA rats.

The supplemental study on Okamoto hypertensive rats was performed in the same way as above, using a dose of 25 mg / kg for the standard compounds and the compounds tested.

In examining the data presented, the following can be concluded: 1.

The two standard compounds, methyldopa and guanethidine and the tested compound A, all significantly reduced the blood pressure of Goldblatt, DOCA and Okamoto hypertensive rats.

142751 7 2.

Methyldopa has approximately the same antihypertensive effect on Goldblatt and DOCA rats and was most potent.

Third

Compound A appears to be the most active against Okamoto rats. TOXICITY

LDpjQ against mice is determined at 1.0 g by oral administration and 0.5 g by intraperitoneal administration.

8 φ 142751

--- Η X

Μ • Η Η Ο «η, ρ ou) a) ininfam'iocowHN (ri5) Μ« V ft f \ Μ ^ · »» · »·» Λ · »·» -CT · Ή, y NrlOVON (Tirl <fNriHO «3 - Η d >> CM rH γΗ ri d II + IIIII« III · II +?

40 * -— <U

Zj - d i φ covo <i-inMt-coisfo <i- <i-crtCT \ ^ o. __i fH Si · * · * · * · * · * · * · · * · * · ** · ** · * · 6 h 0 w ^ inoo ^)! AcriiA ^ N (\ ic \ jvoN ^ φ

2 I> d CO ΝΛ CM H <f KO (Λ H W H

.§ -P d 8 I I I I I I I I I I I I I I η H * fcQ __ - --- - 0

+ 0-3 · Η N O iftiftV) H <t O O ri> MO sins S

^ n d bD ^ ΙΛ ^ h n <t cm 'm o' VQ1 o \ ol Vfl o '<T n id W 2 * ri <f M W H CM Η KO CM CM Η Η 0

toftd · Ηί! I I I I I I 1 I I ί I 1 1 I _L

° d <H do-- “0 m 0 d d <t-ocTiocoN-ioo4S'iScnw ^ i

Tic! »~ -„ ø CM Ot ^ CMHOLnb- <i-OO <y0t ^ OOOd

-1.43.H ^ g. CMCMH Η ΝΛ CMHH O

g d +11111111 + 11111 ^ ______Cu, OCQ® ^ +3 0 ^ S CQH +!

m'ø + j <{· D ^ vOtOC ^ tAinHWrlfO-ilOOOt'CJCM

t) CM <fCOK'iCOfOCOinH (T \ CMOHCMHH

d d Ti CMHCMHCMHCMCMHCMCMCMCMCMCM CQ

S d H <+1 .Ω CD d ¢ .. r! y «—v ci Pi

+> O d bO ITvOOVOfOMDCMHCOOOJMOICMOfO

ØCHO K 00 <! - Ht> -03CMlMnHH'iOinOmO ^ bO CH a CMHHHCMHCMCMHHCMHCMHCM> 1 island a ____—-— ft H +> +> · η d --- “£ M w 0 d ό

j 0 s-p>, +> (JiHHF> O! TiNU) (nH (f \ <rN0D® O

H P <w 0 d £ <f KwPisi ^ intnOioøONi-jcoqH

CQ & d + 5¾ CMHdHCMHCMCMHHCMHCMr-tCMd <P 0 X d 3___ m

ΈΛ B, d> »0 Q .—— S

00 0 d H W d d 3-P 0¾ fO0CMCOCTiWNOCMm <l-CMN0 <r ra d d H d CM ini ^ 0IStOI> - | C \ C \ linPOO) ^ HO) HTj

0 d Ο 0 + * CMHHHCMHCMCMHCMHHCMHCMH

> 0H d-- 9.

Hfrj 0 Tj ocfl "H -hpd cMmøOH4øou> N (DC- ^ qø ra jiu φ g; incOffiOiOincMHCMOicivfcMH nl 0d 0 OJHCM CMCMCMCMCMCMCMCMCMCMCMCMCMCMCMCMd 0 d - ^ 0 g ç n Η · Η 0 0Ϊ \ O MO CM -CM 'OMOCMCM-CM * d>, 0 d O bO CM 00 00 CM 00 00 d> bO O d S «-P d P -----— °' d ώ · Η w 0 Ti U'- 'rn HSdi ω 5 fl-H fl η O 2 H SBO Η Η H 8

0 d ^ 0 Ο Ο B

d 0 0 d d ft 2 ΰ d +> mfl S -P + d d d 0 · Β £ 3 3 Sp a ¢)!> Μ d Ο00 · Η · Η Oøøødvj Ød

u OPiftdd OftftPdd d-P

Ο Ο Ο · Η · Η> w ^ Ο Ο Ο · Η d d fe ddini! ^ · * 1! dddd + J <! <i! + o

Od +! ΰ dddOi! +! +! 5 ·? -Ρ £ * + 3 + 300dd + d + 300dd En®

^ .003000 ^ .0003300 hil HSS66føFøHSSSOOPn.fc + W

_ ______ _____—. ,, ---- «φ · Η

--- OH

d I +> d R

o d -P rQ +5 «8 § 0 H 0

+> 3 H

H d ° +1. £ ω 0 0 · Η d <^ K.

1g "g 0 So.

S3 O Q

9 -, - ρ-τ — j —------ U2751

• orn rorn Ο Ο ro CO CVjCO'MlO'd'OrlCO

03 J4 CM «IS« O «CO« Η «VO« CM «

00CMCMH-d-CMO HOrMinHHMCVI • Η -Η Η H CM Η Η CM

QH +1 +1 +1 +1 +1. +1 ____ ten. .

Λ -------

<1- I

CM Ο σ ^ Η -d "Is Η Ο 00 Ν 1Γ \ CO 03 rO Η -ρ Μ m« στ «m - ο« <(· «σ>« νο 0 ° 3 CM CM Η VO CM CM CMHCMCOHCMCMin

! - *> Η Η H CM Η Η H CM

I ΟΟΗι + Ι +1 +1 +1 +1 +1 +1 d -------- 'ø ftø · I £ £ <η -ρ οοω * κ> * σν * Η co i σ »* σ »Σ_ι 0 0, ί4 Η« * »Ι <3« CO «Η« Ο «Ο«

high η cd 03 cM-d- (jrCMinNirrOOrioinoocM

-p ρ HH HCTrHHHHHHHHHCM CM

cd C cd PH +1 +1 +1 +1 + l +1 +1 Hi Hi! --------- o cd dl * * ...

HH cd co o cocoScois-d-jfjH CO CM tho CM

hi +3 p>, ¾ in «is - * ·> * *, ·· - * *

o> 03 EM CM-d- COn (OOrOt \ imdK3lciNlS

rd .η ϊ> νΗ H CM H CO O] Or H <f H 00 H -d * CM

ho +1 CO Η +1 H-H Η +1 Η +1 CM +1 Η +1 CM +1 H _______—- 1 ----— cd d

H 6 £ I

on B -p mor * ro vo * <T> o * o * l> - K +> øracMcTivoocMmcMvocM-d-cMOinm

? Ch p hh o h in cm m o h -d- η o CM

on CL), ¾ Q H +1 H-H H -f-l H +1 CM +1 H +1 CM -Η H

60 03> i! __________ osh h o H-d-m oo o m is ooo Η h d o -P .¾ in «* - $« * ·>. - S * # C- ~ m ,,

P ^ H h bhouihkcmS inS codin * hk «^ MM

> 40 n 1>, H Η στΗ H CM d -d "H IS H VO IS _" _> Ut- P CO H +1 CM + I 00 -H CO +1 CM +1 VO + | d CM fafafa

p CM O, ¾ Η Η Η H CM + I

-p «Η 0 -------—--- 1- * 133

H 60 H I * S

CM OOØ HO, _ _ „* H + i o-PinooiiiomcrrincMcri H HC0W +> 0Λ K3« m ·>! »! - "- - ~ ~ ω h s 0 cd 0 cm vo -d- co HHOcocnmHiniscr>

pn (D * CQ Cd -Η · Η H C \ j VD CM VO O Η ΙΛ Η Η H S

<tj <J · f-ι Ή QiH +1 rH +1 Η +1 (H + I CVJ + I iH + l C \ l + | CD

EH * d cd -d Λ __._______ rj • Η -H ^ S CM d 0¾ CM I * ^ h 3 o CMH * (O * or -d- -d- m <J \ æ ^ ·

J4 p> + 3J4cD «in« cM «IS« -d -CM «IS«!> - P

03 a 0 island CM CTr -d "VO OrtMCOOinNIDOdCM 10 H cd H! >> H HH HCMHHCMHHCMCMCM Ϊ! 0 HH H CO H +1 +1 +1 +1 +1 +1 +1 +> O o _____-_____ 0 - PP -P — yyyy 0 s 0 ip cd +4 b * o .h · *

h co p3 Hcrrcosmins-comsmmso H

η ρ ø, i4m «vO« H «IS« H «00« CM «-P

0 cd 0 CM O H H CM in i — I CO CM —d "H CM CM m d 0

y) P> -HH HH Η Η H CM 0 P

O-P H PH +1 +1 +1 +1 +1 +1 +1 Η P

o _ H 0 .34 P o-- g ft ø I Λ'- 'HØ O CMOOmvOOcMHinvO-d-COHO 0 H> P3, ii!' £> «0« -d '«Η« in · * H «IS ·> D

ο-H ØØCMmCMHCMvOCMOCMCTrCMCMCMS O

p) w >> H Η Η Η Η Η H cm

| SE 'H

CO Ρ3 __L_J ________—- -------- 03 0 ω m m HH ^ 4 oism «tn - ®

0 ØS. O M0 CM C0 CM 00 S

p O 60 CM S

o h a q --------- «Η 0 d d" r C / 3 cd cd * H * H tk H ^ d. a H H ^ to ΗΟ ° ϊϊ ^^. w Η θΗΗϋϋ <4 <!

d O d Η Η -Ρ -P

H g P> >>! S ø 0

h odil-d d dPP

p O-P + iOd o - ^ .000 d do o fe Hs ^ g g O o fa fa 10 142751

ø ό OirO OJ 00 C * - <Τ <T <t "H CM 03 CM t> - (OfO

• -μ, ίί! CM - O - ro - H - CM - <f “if)“ ^ * m EY CM IO CM O CM VO CM C * - CM m CM 03 CM IO CM 03 H CM! >> · Η Η Η Η H, ./7 ,, cd coh + l +1 +1 +1 +1 +1 + l +1 H ____________—- cd 1 Sk s -p coco * cm S 10 co ^ ^ * »- *, ^ m ° cd EY Λ! H - IO -03 - CO »O -Oi -CM -CO · I + 3 om d \ Oitt) rICM NCM ^ 0 \ · ίΚ) ΝΗ

1 CO -Η -H HH HH HH H, H H HH

§ QH +1 +1 +1 +1 +1 +1 + l + l -PØ + d H __... ______— 0 '"Τ' X, ~ m Search co ό 03 i 4 S æ CM æ Η XI N li H <r S5 ^ -P JsJ CM H C- - <l · - CO - ro - - + - 03 “CO · Λ d I mm cm - h 03 in o HH i> - - +« i> * ) ^! £> ΙΤΜ <i 0>) H 03 H, HH cm H HH ^ / 7 * H j! 7 * ° V7 about CO H +1 +1 +1 +1 +1 +1 +1 + l OH #___ π -------

Ω 0 P I * g * S

^ Μ Η -P CO-i O CO <f <f O ® H 03 ffl N N ® C ^ -CO H

U 5 S3 ^ S «H ri S« H uC S VO H U> S CO- O08 g, * 1 “S3 +, il il il il il +1 +1 ooo

QP P4 PU ______ \ J 3 / V

h ^ ----—--: ““ S 5 I * S ° co + I · “i m ° - le ^ m” · R “- 2 ^ * * *

o P m m tom aio -im N® Hin ffiN ^ 399 ^ * S

* 13 .2 i? S il Hil H + I Nil HH NilNilN + 1 æ £ 31 ”______ s -P- +, α o ό g S $ 0 °° OX m, 5sj C0 ° - OOO CM CM CM O 1 (3 30 ® 0 30 4 IflCM g—-

_i fonr, »m (ti 0] H O Η ** C7 \ · * C ** - · * -Ct“ · * GO * »VQ · * CT \ · i> -P

ro H HH Η H - + H -4; HOT H00 Η Η Η OHO lo H Ø Η ΩΗ + 1 CM Η Η Η Η Η 3 X3 0 PI ECO-P o +1 +1 +1 + i +1 + + l, ~ h H -ø & £ -P il _____._

9 2 + m> cM ~ i CD 0-P

H g P CO O COD'- XI H ro ^ ίϋ ^ ω ^ _T

M ft ^ ø -p ^ m-oi-co-m-ft -ft! - “<f

vjcMTj mm cm in co cm o 30 ir \ 0 \ cMrnHcvjiOH

ra d >> h η h cm cm h cm h oo h ro η η h cm dp -HP § CO Η +1 +1 +1 +1 H + I CM +1 CM +1 CM + I © 0 jq ^ H p

£ S ________—--- Η P

-p ra I ^ 2 p -P comrococM- + ro ^ 03CMcMroooroHinm

_l n MrisiO3-O3-O-C0-O-H-O3-O3 * P

TiP) tender HCM H- + CM H HCM CM CM CMHHHHINO

Η Η Η Η Η Η Η Η Η H

& 0 - X! QH +1 +1 +1 +1 +1 +1 +1 +1 r, OP T2 0 O ---- ra -rajj O <t O 03 CM 03 cm o- + Hin COCOHO 00 03 «• n pw - ίο - all - in - in - o - £ M; h HP mm cm ro cm 03 cmio cmcm cmcm cmcocmio cmco © oi> jH Η Η Η Η Η H, -3 ^ Φ MH +1 +1 +1 +1 +1 +1 + l +1 tjlj

ra> ____—--- H

t> »H d co m 5o cq ho, Zi η -π X o i> - m m minrn ^ 0 m \ o CO CM CM“ CM - w p O above CM CD cd

OH S

CQ ά ri m

H O 0 0 © Η H

0 O Pi Pi P) TJ H

H O O O Η H

d HHHXIQ''5! '' 5! Η O Η Η H +5 +5 o 2 ^ -. >,!>,!> »0 ø P OHx! / 1 +3 d 8¾1¾

n O-p-p-P ø EPP

pt, ^ .pø 0 0 2 3 O O

H-P s S s o O fa fe 11 142751 TABLE 4

Systolic and diastolic mean blood pressure (in mmHg) before and after treatment with the compounds

Compound Number Blood Pressure (h after treatment) ___0 11 1/2 3 6 24 α-Methyldopa 6 Systolic 246 211 193 174 2J6 25 mg / kg ___________ Diastolic 211 _179____162 149 207___

Guanethidine 3 Systolic 228 .170 223 210 251 25 mg / kg _________________ Diastolic_192 __150____188 _182 219____

Conn. A 6 Systolic 239 177 167 177 208 25 mg / kg ___ Diastolic 212 155 141 146 169 TABLE 5

Mean blood pressure for groups of Okamoto rats and% blood pressure modification_

Compound Blood pressure (after treatment ____0 1 1/2 3 I 6 24 α-Methyldopa 6 blood pressure 234 200 183 166 226 __25_mg / kg

Guanethedine 3 blood pressure 216 163 211 201 240 __25_mg / kg _____________________- 24z5_ -_2i_3 ..-_ §z9 ___

Conn. A 6 blood pressure 230 170 158 167 195 25 mg / kg% modified. -26.1 -31.3 -27.4 -15.2 |